Showing papers by "Fifth Affiliated Hospital of Xinjiang Medical University published in 2019"

MiR-34b Protects Against Focal Cerebral Ischemia-Reperfusion (I/R) Injury in Rat by Targeting Keap1.

Abstract: Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. Understanding the mechanism of ischemia/reperfusion (I/R)-induced oxidative stress injury may provide new treatment for ischemic stroke. Kelch-like ECH-associated protein 1 (Keap1)/ NF-E2-related factor 2 (Nrf2)/ antioxidant response elements (ARE) signaling pathway has been considered to be the major cellular defense against oxidative stress. In the present study, our objective is to evaluate the molecular mechanism of miR-34b/Keap1 in modulating focal cerebral I/R induced oxidative injury. miR-34b was predicted to target the 3'-UTR of the rat Keap1. After focal cerebral I/R, miR-34b expression was downregulated in a time-dependent manner; miR-34b overexpression ameliorated I/R-induced oxidative stress injury in middle cerebral artery occlusion (MCAO) rats by reducing the infarction volume, the neurological severity scores, the levels of nitric oxide (NO) and (3-nitrotyrosine) 3-NT while increasing total (superoxide dismutases) SOD and manganese SOD (MnSOD). Through direct targeting, miR-34b could suppress the protein levels of Keap1 and increase the protein levels of Nrf2 and heme oxygenase (HO-1). Regarding the molecular mechanism, Keap1 overexpression exacerbated, while miR-34b improved H2O2-induced oxidative stress injury; the effect of miR-34b could be partially attenuated by Keap1 overexpression, suggesting that miR-34b modulated oxidative stress injury in vitro and in vivo through targeting Keap1. Taken together, we demonstrate that miR-34b protects against focal cerebral I/R-induced oxidative stress injury in MCAO rats and H2O2-induced oxidative stress injury in rat neuroblast B35 cells through targeting Keap1 and downstream Keap1/Nrf2 signaling pathway. We provided a novel mechanism of focal cerebral I/R injury from the perspective of miRNA regulation.

Integrative Analysis Toward Different Glucose Tolerance-Related Gut Microbiota and Diet.

Abstract: Objective: There is evidence that type 2 diabetes (T2DM) is affected by gut microbiota, and gut microbiota diversity modified by diet. To investigate its modifications in Uyghur patients with different glucose tolerance, we enrolled 561 subjects: newly diagnosed T2DM (n = 145), impaired glucose regulation (IGR) patients (n = 138) and in normal control (NC) population (n = 278). Methods: The nutrient intake in food frequency questionnaire was calculated by R language. The regions V3-V4 of 16S ribosomal RNA were sequenced by using Illumina Miseq platform. Sequences were clustered by operational taxonomy units, gut microbiota composition, and diversity was analyzed. Correlations between bacterial composition at different level and dietary factors were evaluated. Results: The α-diversity was highest in NC, followed by T2DM and IGR; β-diversity distinguished between patients and NC. Compared to NC, Saccharibacteria was significantly increased in T2DM and IGR. Deferribacteres was significantly increased in T2DM compared to NC and IGR. Veillonella, Pasteurellaceae, and Haemophilus were over-represented in IGR. Abundance of Bacteroidetes was negatively correlated with LDL-C; Abundance of Tenericutes was negatively correlated with hip circumference and total cholesterol, positively correlated with HDL-C and cake intake; Actinobacteria was positively correlated with BMI and folic acid intake, negatively correlated with oil intake. Firmicutes was negatively correlated with beverage and alcohol intake. Spirochaetae was negatively correlated with fungus, fruits, beans, vitamin C, dietary fiber, and calcium. Fusobacteria was positively correlated with beans intake, and was negatively correlated with fat intake. Proteobacteria was positively correlated with tuber crops intake. Synergistetes was positively correlated with cholesterol, nicotinic acid, and selenium intake. Deferribacteres was negatively correlated with magnesium intake. Conclusions: At the phylum and genus level, the structure and diversity of intestinal microbiota of T2DM and IGR was altered, the number of OTUs, the relative abundance, and diversity were all decreased. The gut microbiota of the newly diagnosed T2DM, IGR, and NC were related to age, blood lipids, BMI, blood pressure, and dietary nutrient intake. Unbalanced nutrient intake in the three groups may affect the structure and abundance of the gut microbiota, which may play a role in the occurrence and development of T2DM.

Metagenomics and Faecal Metabolomics Integrative Analysis towards the Impaired Glucose Regulation and Type 2 Diabetes in Uyghur-Related Omics

Abstract: Objective. Gut microbiota and their metabolites play an important role in the development of type 2 diabetes mellitus (T2DM). This research was designed to study the relationship between gut microbiota and faecal metabolites of Uyghur newly onset T2DM and impaired glucose regulation (IGR) patients. Materials and Methods. A total of 60 different glycemic Uyghur subjects were enrolled and divided into T2DM, IGR, and normal glucose tolerance (NGT) groups. Metagenomics and LC-MS-based untargeted faecal metabolomics were employed. Correlations between bacterial composition and faecal metabolomics were evaluated. Results. We discovered that the composition and diversity of gut microbiota in newly onset T2DM and IGR were different from those in NGT. The α-diversity was higher in NGT than in T2DM and IGR; β-diversity analysis revealed apparent differences in the bacterial community structures between patients with T2DM, IGR, and NGT. LC-MS faecal metabolomics analysis discovered different metabolomics features in the three groups. Alchornoic acid, PE (14 : 0/20 : 3), PI, L-tyrosine, LysoPC (15 : 0), protorifamycin I, pimelic acid, epothilone A, 7-dehydro-desmosterol, L-lysine, LysoPC (14 : 1), and teasterone are the most significant differential enriched metabolites. Most of the differential enriched metabolites were involved in metabolic processes, including carbohydrate metabolism, starch and sucrose metabolism, phenylpropanoid biosynthesis, and biosynthesis of amino acids. Procrustes analysis and correlation analysis identified correlations between gut microbiota and faecal metabolites. Matricin was positively correlated with Bacteroides and negatively correlated with Actinobacteria; protorifamycin I was negatively correlated with Actinobacteria; epothilone A was negatively correlated with Actinobacteria and positively correlated with Firmicutes; PA was positively correlated with Bacteroides and negatively correlated with Firmicutes; and cristacarpin was positively correlated with Actinobacteria; however, this correlation relationship does not imply causality. Conclusions. This study used joint metagenomics and metabolomics analyses to elucidate the relationship between gut microbiota and faecal metabolites in different glycemic groups, and the result suggested that metabolic disorders and gut microbiota dysbiosis occurred in Uyghur T2DM and IGR. The results provide a theoretical basis for studying the pathological mechanism for further research.

PKM2-regulated STAT3 promotes esophageal squamous cell carcinoma progression via TGF-β1-induced EMT.

Abstract: Recent studies have demonstrated pleiotropic roles of pyruvate kinase isoenzyme type M2 (PKM2) in tumor progression. However, the precise mechanisms underlying the effects of PKM2 on esophageal squamous cell carcinoma (ESCC) metastasis and transforming growth factor β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) remain to be established. In this study, we observed upregulation of PKM2 in ESCC tissues that was markedly associated with lymph node metastasis and poor prognosis. High PKM2 expression in tumor tissues frequently coincided with the high pSTAT3Tyr705 expression and low E-cadherin expression. Furthermore, altered PKM2 expression was significantly associated with proliferation, migration, and invasion of ESCC cells, in addition to expression patterns of EMT markers (Snail, E-cadherin, and vimentin) and pSTAT3Tyr705 /STAT3 ratio. Overexpression of STAT3 significantly attenuated the effects of PKM2 knockdown on cell proliferation and motility as well as expression of pSTAT3 Tyr705 and EMT markers. Consistently, stable short hairpin RNA (shRNA)-mediated silencing of PKM2 reversed the effects of TGF-β1 treatment, specifically, upregulation of PKM2, phosphorylation of STAT3 at Tyr705, and increased EMT, migration, and invasion. We propose that PKM2 regulates cell proliferation, migration, and invasion via phosphorylation of STAT3 through TGF-β1-induced EMT. Our findings collectively provide mechanistic insights into the tumor-promoting role of PKM2, supporting its prognostic value and the therapeutic utility of PKM2 inhibitors as potential antitumor agents in ESCC.

Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial

Abstract: N-acetylcysteine is a classic mucolytic agent. This study aimed to investigate the efficacy of N-acetylcysteine on reducing the risk of exacerbations in bronchiectasis patients. A prospective, randomized, controlled trial was conducted between April 1, 2014 and December 31, 2016 in five general hospitals in Shandong Province, China. Adult bronchiectasis patients with at least two exacerbations in the past year were potentially eligible. Patients were randomly assigned to receive oral N-acetylcysteine (600 mg, twice daily, 12 months) or on-demand treatment. A total of 161 patients were eligible for randomization (81 to the N-acetylcysteine group and 80 to the control group). During the 12-month follow-up, the incidence of exacerbations in the N-acetylcysteine group was significantly lower than that in the control group (1.31 vs. 1.98 exacerbations per patient-year; risk ratio, 0.41; 95% CI, 0.17–0.66; P = 0.0011). The median number of exacerbations in the N-acetylcysteine group was 1 (0.5–2), compared with 2 (1–2) in the control group (U = − 2.95, P = 0.003). A total of 24.7% of the N-acetylcysteine group patients and 11.3% of the control group patients remained exacerbation-free throughout the 12-month follow-up (χ2 = 4.924, P = 0.026). Compared with the control group, the volume of 24-h sputum in the N-acetylcysteine group was significantly reduced (t = − 3.091, P = 0.002). Additionally, the N-acetylcysteine group showed a significant improvement in the quality of life. No severe adverse events were reported in the intervention group. The long-term use of N-acetylcysteine is able to reduce the risk of exacerbations for bronchiectasis patients in Shandong Province, China. The results of this study should be verified in a larger randomized controlled trial. ClinicalTrials.gov (NCT02088216) (Registered date: March 5, 2014).

miRNA-15a regulates the proliferation and apoptosis of papillary thyroid carcinoma via regulating AKT pathway.

Abstract: Aim Aberrantly expressed microRNAs (miRNAs) are involved in many diseases including cancer. The expression of miR-15a was reported to be downregulated in papillary thyroid carcinoma (PTC) compared to control tissue. However, the mechanism underlying this downregulation remains unclear. Methods The effects of miR-15a on the proliferation and invasion of PTC cells were evaluated by CCK-8 and transwell assays, respectively. Expression levels of AKT and rearranged during transfection (RET) in cells were assessed using Western blotting. The correlation of RET and miR-15a was validated by luciferase reporter assay. Moreover, in vivo assay was performed to demonstrate the effect of miR-15a on tumor growth. Results We confirmed that the expression of miR-15a was significantly lower in PTC tissue than that in normal tissue. Overexpression of miR-15a notably inhibited PTC cell proliferation and invasion via promoting apoptosis. Additionally, RET was found to be a target of miR-15a and this correlation was confirmed by dual-luciferase assay and Western blot. Furthermore, in vivo study revealed that overexpression of miR-15a inhibited tumor growth via downregulating the levels of RET and phosphorylated AKT. Conclusion In the present study, we demonstrated that miR-15a played an antitumor role in regulating PTC via targeting RET/AKT pathway. Therefore, miR-15a may serve as a potential molecular target for the treatment of PTC.

The 5-Lipoxygenase Inhibitor Zileuton Protects Pressure Overload-Induced Cardiac Remodeling via Activating PPARα

Abstract: Zileuton has been demonstrated to be an anti-inflammatory agent due to its well-known ability to inhibit 5-lipoxygenase (5-LOX). However, the effects of zileuton on cardiac remodeling are unclear. In this study, the effects of zileuton on pressure overload-induced cardiac remodeling were investigated and the possible mechanisms were examined. Aortic banding was performed on mice to induce a cardiac remodeling model, and the mice were then treated with zileuton 1 week after surgery. We also stimulated neonatal rat cardiomyocytes with phenylephrine (PE) and then treated them with zileuton. Our data indicated that zileuton protected mice from pressure overload-induced cardiac hypertrophy, fibrosis, and oxidative stress. Zileuton also attenuated PE-induced cardiomyocyte hypertrophy in a time- and dose-dependent manner. Mechanistically, we found that zileuton activated PPARα, but not PPARγ or PPARθ, thus inducing Keap and NRF2 activation. This was confirmed with the PPARα inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPARα knockdown abolished the anticardiac remodeling effects of zileuton in vivo. Taken together, our data indicate that zileuton protects against pressure overload-induced cardiac remodeling by activating PPARα/NRF2 signaling.

Association of Dietary Patterns with Type 2 Diabetes Mellitus among Middle-Aged Adults in Uygur Population of Xinjiang Region.

Abstract: Observational and interventional studies have showed associations between dietary patterns and the risk of type 2 diabetes (T2DM). The aim of the present study was to identify dietary patterns and examine their association with incident of T2DM and physiopathologic mechanism in the Uygur population of Xinjiang, China. A community-based case control study in Urumqi, Xinjiang Uygur Autonomous Region, China. We enrolled 836 Uygur adults (345 newly diagnosed T2DM and 491 healthy controls) receiving physical examination in community health service centers. Dietary patterns were evaluated using a validated 121 items semi-quantitative food frequency questionnaire (SQFFQ). Dietary patterns were identified by exploratory factor analysis. Data on demographic, anthropometric, socioeconomic characteristics were collected. Homeostasis model assessment index for insulin resistance (HOMA-IR) and for β cell function (HOMA-β) were calculated. Multivariate logistic regression were used to estimate the associations between dietary patterns and the risk of T2DM and multiple linear regression were used to evaluate the association between dietary patterns and fasting plasm glucose (FPG), fasting insulin (FINS), HOMA-IR and HOMA-β, adjusting for confounding factors. Five major dietary patterns were identified: (1) the "vegetable and tubes" pattern; (2) the "fruit and nut" pattern; (3) the "refined grains and meat" pattern; (4) the "dairy, legume and egg" pattern; and (5) the "oil and salt" pattern. Logistic regression results demonstrated that the "vegetable and tubes" dietary pattern and the "fruit and nut" dietary pattern were related to T2DM, OR values were 0.223 (95% CI: 0.135-0.371), 0.160 (95% CI: 0.093-0.275), respectively. The "refined grains and meat" dietary pattern and the "oil and salt" dietary pattern were related to T2DM, OR values were 6.146 (95% CI: 3.217-11.739), 9.554 (95% CI: 5.668-16.104), respectively. Multiple linear regression analysis showed that the above five dietary patterns were related to log (FPG), β values were -0.040, -0.039, 0.028, -0.010 and 0.036, respectively, all p<0.05. The "vegetable and tubes" pattern, the "fruit and nut" pattern, the "refined grains and meat" pattern and the "oil and salt" pattern were related to log (HOMA-IR), β values were -0.061, -0.060, 0.045, and 0.042, and were related to log (HOMA-β), β values were 0.071, 0.063, -0.035 and -0.070, respectively, all p<0.05. The "refined grains and meat" dietary pattern and the "oil and salt" dietary pattern may be the important reason for the rapid increase of T2DM incidence among Chinese Uygur residents. Our findings suggest that modifying dietary patterns could reduce T2DM incidence in the adult Uygur population.

Cell Ratio Differences in Peripheral Blood between Early- and Late-Onset Parkinson’s Disease: A Case-Control Study

Abstract: Objectives. To explore the differences of immune disorders in peripheral blood between patients with early-onset Parkinson’s disease (EOPD) and late-onset Parkinson’s disease (LOPD). Methods. We retrospectively reviewed medical records of Parkinson’s disease (PD) patients and healthy controls between June 2002 and July 2017. At last, we included 117 PD patients who were divided into EOPD and LOPD according to whether onset age of PD was after 50 and 99 controls divided into E-Control (match for EOPD) and L-Control (match for LOPD) according to whether their age was after 53 which was onset age plus median of disease duration. We compared the ratios of cells between multiple groups and performed the multinominal logistic regression analysis to explore the relationship between ratios and subtypes of PD. We also carried out the receiver operating characteristic (ROC) curve analysis to estimate the diagnostic value of the variable. Results. Lymphocyte-red blood cell ratio (LRR) was lower in LOPD compared with that in EOPD or L-Control. LRR was also negatively associated with LOPD (OR: 0.623; 95% CI: 0.397–0.980; ). The ROC curve analysis showed the optimal cutoff value of 4.53 (×10−4) of LRR for discrimination of LOPD versus L-Control (sensitivity: 0.596, specificity: 0.764). The area under curve (AUC) was 0.721. As for LOPD versus EOPD, the optimal threshold of LRR was 4.10 (×10−4) (sensitivity: 0.516, specificity: 0.745). AUC was 0.641. Conclusions. Peripheral immune disorders might play an important part in the pathological progression of LOPD. Also, LRR has potential diagnostic value.

Three GLI2 mutations combined potentially underlie non‐syndromic cleft lip with or without cleft palate in a Chinese pedigree

Abstract: BACKGROUND Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect. Its etiology is complex and it has a lifelong influence on affected individuals. Despite many studies, the pathogenic gene alleles are not completely clear. Here, we recruited a Chinese NSCL/P family and explored the candidate causative variants in this pedigree. METHODS We performed whole-exome sequencing on two patients and two unaffected subjects of this family. Variants were screened based on bioinformatics analysis to identify the potential etiological alleles. Species conservation analysis, mutation function prediction, and homology protein modeling were also performed to preliminarily evaluate the influence of the mutations. RESULTS We identified three rare mutations that are located on a single chromatid (c.2684C > T_p.Ala895Val, c.4350G > T_p.Gln1450His, and c.4622C > A_p.Ser1541Tyr) in GLI2 as candidate causative variants. All of these three mutations were predicted to be deleterious, and they affect amino acids that are conserved in many species. The mutation c.2684C > T was predicted to affect the structure of the GLI2 protein. CONCLUSION Our results further demonstrate that GLI2 variants play a role in the pathogenesis of NSCL/P, and the three rare missense mutations combined are probably the potential disease-causing variants in this family.

The Number of Regulatory B Cells is Increased in Mice with Collagen-induced Arthritis.

Abstract: The aim of this study is to investigate changes in regulatory B cells (Bregs) and the expression of related cytokines such as interleukin-10 (IL-10) and transforming growth factor (TGF)-β in a mouse model of collagen-induced arthritis (CIA) A total 20 DBA/1 mice (6-8 weeks old) were randomly divided into control and CIA disease groups For the CIA disease group, animals were injected intradermally with chicken collagen type II and complete Freund's adjuvant The calculated arthritis index score of the CIA group was significantly higher than that in control group Hematoxylin and eosin staining showed tumid synovial cells with irregular arrangement and obvious hyperplasia, with a high degree of inflammatory cell infiltration in CIA model group Cytometric bead array technology and quantitative RT-PCR indicated that the levels of IL-10 and TGF-β in serum, and synovial cells were significantly increased in the CIA group The proportion of Bregs in the spleen of the CIA group was significantly increased compared to the control group In conclusion, our findings demonstrate that the number of Bregs and the expression of TGF-β and IL-10 are enhanced in mice with CIA

Application of protein chip combined with SELDI‑TOF‑MS detection to investigate serum protein expression in patients with silicosis fibrosis

Abstract: The present study aimed to observe the identification of biomarkers of silicosis based on the differentially expressed serum proteins between normal healthy individuals and patients with silicosis fibrosis. A total number of 20 patients with clinically diagnosed silicosis were screened, which were designated as the foundation treatment group. In addition, 20 age-matched healthy patients attending a check-up at the physical examination department were selected. Serum samples were obtained and a combined protein chip with surface-enhanced laser desorption ionization flight mass spectrometry was applied to perform serum analysis. Data preprocessing, screening differences in peak, hierarchical cluster analysis, Principal Component Analysis, construction of a decision tree model, and prediction based on the differences between peaks corresponding to proteins were performed to analyze the data. The results revealed differences in the proteins in serum between the normal group and the group prior to foundation treatment prediction. The corresponding names of the protein peak, predicted protein, and gene name were as follows: M1948_00, complement c3 frag, C3; M2017_02, amyloid-βa4 protein, APP; and M2879_56, hepcidin, HAMP. Differentially expressed serum proteins in the normal group and the basis treatment group were predicted, including M2017_02, amyloid-βa4 protein, APP; M2879_56, hepcidin, HAMP; and M3224_97, fibrinogen-α chain frags, FGA. The differentially expressed serum proteins in the group prior to basis treatment and the group following basis treatment were predicted, including M2001_69, amyloid-βa4 protein, APP; M2017_02, amyloid-βa4 protein, APP, M4144_81, plasma protease c1 inhibitor frag, and SERPING1. In conclusion, there were differences in the proteins in serum between the patients with silicosis fibrosis and healthy individuals.

Investigation of the association between obesity and insulin-induced gene 1 polymorphism at 7q36.3 region in Uygur population in Xinjiang, China.

Abstract: BACKGROUND Obesity is a common heritable trait and a major risk factors of chronic and metabolic diseases. Insulin-induced gene 1 (INSIG1) is known to play important roles in cholesterol and triacylglycerol (TAG) metabolism. In the present study, our primary objective was to explore whether the single nucleotide polymorphisms (SNPs) in INSIG1 gene were associated with obesity in Uygur subjects, in Xinjiang, China. METHODS We designed a case-control study including 516 obese patients and 463 age- and sex-matched control subjects. Three SNPs (rs2721, rs9767875 and rs9719268) were genotyped using TaqMan SNP genotyping assays. RESULTS For rs2721, the distribution of genotypes, dominant model (GT + TT vs GG), recessive model (TT vs GT + GG) showed significant differences between obese patients and the controls (P = 0.008, P = 0.005 and P = 0.035, respectively). For rs9719268, the distribution of genotypes showed significant differences between obese patients and the controls (P = 0.004). The dominant model (GT + TT vs GG) of rs2721 and rs9719268 GT genotype remain significantly associated with obesity after adjustment for confounders (OR = 1.393, 95% CI = 1.047-1.853, P = 0.023; OR = 1.631, 95% CI = 1.059-2.512, P = 0.026). The TG levels were significantly higher in rs2721 GT/TT genotypes than that in GG genotypes (P<0.05). CONCLUSIONS Rs2721 and rs9719268 of INSIG1 gene are associated with obesity in Uygur subjects. Subjects with GT/TT genotype or T allele of rs2721 and GT genotype of rs9719268 were associated with an increased risk of obesity.